Pd-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine

Abstract

Acyl fluorides have recently gained a lot of attention as robust and versatile synthetic tools in synthetic chemistry. While several synthetic routes to acyl fluorides have been reported, a procedure involving direct insertion of the “fluoro-carbonyl” moiety using a single reagent has not yet been realized. Here we report the preparation of acyl fluorides by palladium-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine under CO-free conditions. 2-(difluoromethoxy)-5-nitropyridine is a stable, colorless solid that can be used as an alternative to the toxic gaseous formyl fluoride, which is commonly used under fluoride catalysis conditions. A wide variety of acyl fluorides are efficiently and safely obtained in high yield (up to 99%). A broad range of functional groups is tolerated under the optimized reaction conditions and the method can be applied to the late-stage fluoro-carbonylation of structurally complex Csp2-iodides, including bioactive derivatives, such as Fenofibrate, Isoxepac, and Tocopherol. Furthermore, the one-pot transformation of aryl-iodides, including drug-like molecules, into the corresponding amides by successive fluoro-carbonylation/amidation reactions, demonstrates the potential synthetic utility of this strategy.

Mechanochemical Deoxyfluorination of Carboxylic Acids to Acyl Fluorides and Successive Mechanochemical Amide Bond Formation

“…The formation of amide bonds from the reaction of acyl halides and amines is one of the most atom-efficient pathways and therefore produces minimal waste in relation to the method mediated by activators. Although acyl chlorides are the most common acyl halides for amidation reactions, the use of acyl fluorides has recently attracted attention because of their stability and facile operation. − The reaction between acyl fluorides and amines is typically performed in the presence of a base in a solvent. − During the optimization of the conditions for the reaction of acyl fluoride 2a and n -butyl amine ( 3a ) to afford amide 4aa , we observed that mechanochemical coupling proceeded smoothly to afford 4aa in 93% yield without any base or solvent (Scheme B). This outcome was similar to that obtained in the presence of Et 3 N (2.0 equiv), yielding 4aa in a 94% yield.…”

Preparation, characterization and reactivity of trifluoromethoxy palladium(ii) complexes

“…4A, eqn (2)). 27 It is likely that β-fluorine elimination of the weakly bound trifluoromethoxy group generates fluorophosgene which might bind to the palladium metal center, followed by insertion of the fluorophosgene into the Pd–Ar bond and a second β-fluorine elimination to give the corresponding acid fluoride.…”

“…7). 27 Considering the Pd(0) complex that could be generated after reductive elimination from Pd( ii ) complex, we also tried the thermal reaction of complex 5a in the presence of 10.0 equivalents of 1-bromo-(4- tert butyl)benzene or 3.0 equivalents of t BuBrettPhos. Again, the formation of the desired Ar–OCF 3 reductive elimination was not observed (Scheme 1, entry 4).…”

“…Because we observed that the 19 F NMR spectroscopic signal for the trifluoromethoxy group in complexes ligated with phosphino ligand such as DPPF or BrettPhos showed a broad peak but became sharper when the temperature for acquitting the 19 F NMR spectroscopy was decreased to À10 1C, it is reasonable to assume that there is a reversible dissociation-coordination equilibrium of the 7). 27 Considering the Pd(0) complex that could be generated after reductive elimination from Pd(II) complex, we also tried the thermal reaction of complex 5a in the presence of 10.0 equivalents of 1-bromo-(4tertbutyl)benzene or 3.0 equivalents of t BuBrettPhos. Again, the formation of the desired Ar-OCF 3 reductive elimination was not observed (Scheme 1, entry 4).…”

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD®/Olah’s reagent under solvent-free conditions

“…Our group has developed various efficient methodologies for the electrophilic [14,15], nucleophilic [16], and radical [17] trifluoromethylation reactions for more than a decade. In recent years, we also reported the direct introduction of an acyl fluoride unit into aromatic compounds by the Pd-catalyzed cross-coupling reaction of aryl, vinyl, and heteroaryl iodides with 2-(difluoromethoxy)-5-nitropyridine [18]. A wide variety of acyl fluorides were efficiently obtained in high yields.…”